Identification of Novel, Drug-like Inhibitors of Hsp90

描述(由申请人提供)：尽管癌症治疗最近取得了进展，但识别新的抗癌治疗药物仍然是一项迫切的需要。热休克蛋白90(Hsp90)是一种分子伴侣，可与多种客户蛋白结合并折叠，包括一些与癌症相关的关键靶点，如BCR-Ab1、Raf-1和SRC家族蛋白，如SRC、LCK和FYN，突变的P53、ErbB2和类固醇激素受体。Hsp90的抑制破坏了折叠过程，导致这些客户蛋白的降解。由于Hsp90客户蛋白在癌细胞生长和存活的关键过程(如信号转导和转录)中非常重要，Hsp90抑制剂可能成为治疗许多癌症的有效化疗药物。这一假说已被格尔达霉素类似物17-AAG和17-DMAG临床验证。然而，这些安沙霉素类似物具有较差的药代动力学性质和非靶点毒性。因此，需要改进的Hsp90抑制剂。这项第一阶段的提案重点是利用Locus的创新计算技术设计的四种新型Hsp90抑制剂系列的合成、生物学评估和结晶学。这项研究的最终建议产品是一种针对Hsp90的口服癌症治疗药物。

DESCRIPTION (provided by applicant): Despite recent advances in cancer treatment, the identification of novel anti-cancer therapeutic agents remains a pressing need. Heat Shock Protein 90 (Hsp90) is a molecular chaperone which binds to and folds several client proteins including a number of key cancer-relevant targets such as the kinases Bcr-Abl, Raf-1, and SRC family kinases such as SRC, LCK and FYN, mutated p53, ErbB2, and the steroid hormone receptors. Disruption of the folding process by Hsp90 inhibition leads to degradation of these client proteins. Because Hsp90 client proteins are so important in processes critical to the growth and survival of cancer cells (e.g., signal transduction and in transcription), Hsp90 inhibitors may serve as effective chemotherapeutic agents against a number of cancers. This hypothesis has been clinically validated by the geldanamycin analogs 17- AAG, and 17-DMAG. However, these ansamycin analogs suffer from poor pharmacokinetic properties and off- target toxicity. Thus, there is a need for improved Hsp90 inhibitors. This Phase I proposal focuses on synthesis, biological assessment and crystallography of four novel series of Hsp90 inhibitors that were designed using Locus' innovative computational technology. The ultimate proposed product of this research is an orally administered cancer therapeutic drug targeting Hsp90.